tbuckley/cabot-search huggingface dataset:
P05.01.B Distribution of the staining agent sodium-fluorescein in cerebral neoplasia - a comparison between intraoperative confocal laser endomicroscopy and in vitro fluorescence microscopy
Authors: M C Brielmaier, J Reifenrath, N Pensel, F Ganster, J Bierlein, A Wagner, J Gempt, J Schlegel
Journal: Neuro-Oncology (2022)

Abstract Background While conventional frozen sections and other ex vivo microscopy always come along with artefacts, in vivo confocal laser endomicroscopy (CLE) offers less invasive, less manipulated imaging of living tissues. Understanding the distribution of the staining agent sodium-fluorescein (NaFl) plays a key role in establishing in vivo CLE as a new opportunity for real-time transmitted, in vivo imaging. By comparing the distribution of NaFl in in vivo and ex vivo CLE to conventional fluorescence microscopy of NaFl incubated tumor cell cultures we gain a better understanding of the staining mechanism. Material and Methods Sodium-fluorescein is the water-soluble sodium salt of fluorescein and is used as a fluorescent tracer in neurosurgery. The staining agent was applied intravenously at the beginning of the surgical procedure. In vivo CLE of the lesion was performed 30 to 50 minutes later and compared to ex vivo CLE imaging and conventional fluorescence microscopy. In addition, different tumor cell lines derived from malignant gliomas and carcinomas, respectively, were incubated with NaFl in vitro and the uptake of the fluorescent dye was monitored over time. Results From initial results, the intraoperative images showed specific fluorescein distribution depending on the architecture of the tumor entity. In most cases, glial tumors demonstrated higher accumulation of the staining agent in the extracellular tumor matrix, whereas the cells of carcinoma metastases appeared to take up NaFl intracellularly. These results were corroborated by NaFl uptake in cell culture experiments. Compared to ex vivo CLE, in vivo imaging offered a faster assessment of the tissue, brighter images and higher staining levels. Due to movement artefacts and the narrow intraoperative imaging time frame, in vivo CLE images were sometimes impaired by lower image quality. Conclusion The specific distribution of the fluorescent agent NaFl allowed for a discrimination between the different neoplastic entities. Images from in vivo and ex vivo confocal laser endomicroscopy showed NaFl uptake in concordance with the results of NaFl incubated cell cultures. Intraoperative, in vivo confocal laser endomicroscopy shows promising first results in the understanding of brain tumor histomorphology in situ. Being faster and less manipulated by artefacts than ex vivo investigations, it opens up wider opportunities for research and intraoperative diagnostics.
OS07.5.A Report from the pooled analysis of the randomized trials NORDIC, NOA-8 and CE.6 on elderly patients with glioblastoma
Authors: T Gorlia, F Oppong, C O′Callaghan, W Wick, N Laperriere, M Weller, J Perry, G Reifenberger, B Tavelin, A E Malmström
Journal: Neuro-Oncology (2022)

Abstract Background The majority of patients diagnosed with glioblastoma are over 60 years old. Three randomized trials addressed the roles of radiotherapy (RT) and temozolomide (TMZ) for these patients. Two, the NORDIC and NOA-08 (N&amp;N) compared RT versus TMZ head-to-head, the third, CE.6, randomized between hypofractionated RT and the combination of RT+TMZ. All showed significant benefit for the TMZ arms, especially for patients with MGMT promoter methylated tumors. An ongoing pooled analysis of these three trials focuses on identifying significant baseline prognostic factors and assess their value for predicting outcome in relation to treatment. The aim is improved selection of elderly patients with glioblastoma for their optimal treament; RT alone, TMZ with or without concomitant RT or palliative care. Methods The data of two phase 3 studies (N&amp;N) were pooled to build a large dataset and findings are compared to CE.6 trial data. A re-assessment of the clinically most relevant MGMT cut-off is performed. The prognostic value of baseline clinical factors and quality of life scores, determined by the EORTC QLQ-30 and BN-20 questionnaires, are investigated. Data is also analysed to account for a possible impact of sex. Results The N&amp;N dataset includes 715 and the comparative dataset (CE.6) 562 patients. Median age for N&amp;N is 71 years and 73 for CE.6. In N&amp;N and CE.6 respectively, 66.2% versus 70.5% underwent resection and 50.9% and 75.3% were on steroids at the time of study inclusion. In N&amp;N, 401 patients received RT alone and 281 in CE.6, while 314 were randomized to TMZ alone in N&amp;N and 281 to concomitant RT and TMZ in CE.6. For N&amp;N MGMT promoter methylation status was successfully determined for 412 (57.6%) and 354 (63.0%) for CE.6. In a first report, patients with the combination of the comorbidities hypertension, diabetes and/or cerebrovascular insult had poorer prognosis when treated with TMZ. Conclusion An ongoing pooled analysis of the trials NORDIC, NOA-08 and CE.6 is expected to identify factors that will improve personalized medicine for elderly patients with glioblastoma. Reanalyzed MGMT promoter methylation data and the role of baseline quality of life for outcome will be reported.
OS07.3.A Phase 1/2 clinical trial of blood-brain barrier opening with the SonoCloud-9 implantable ultrasound device in recurrent glioblastoma patients receiving IV carboplatin
Authors: A Idbaih, A Sonabend, R Stupp, O Chinot, H Dufour, F Ducray, P Menei, J de Groot, C Desseaux, A Carpentier
Journal: Neuro-Oncology (2022)

Abstract Background Low intensity pulsed ultrasound (LIPU) in combination with microbubbles is a promising approach for brain drug delivery. A phase 1/2 clinical study (NCT03744026) was initiated to demonstrate the safety and efficacy of blood-brain barrier (BBB) disruption over a large volume using an implantable ultrasound system (SonoCloud-9) in patients with recurrent glioblastoma receiving carboplatin chemotherapy. Material and Methods The SonoCloud-9 device (Carthera, Paris, France) was placed at the end of tumor resection and replaced the bone flap. The device was activated 9-14 days after surgery for a duration of 270 seconds every 4 weeks until progression or treatment completion, concomitantly with IV DEFINITY microbubbles (10 μl/kg, Lantheus, Billerica, US). The Phase 1 cohort consisted of an escalation of BBB disruption volume by activation of 3 (n=3), 6 (n=3), then 9 (n=3) emitters of the device. Dose limiting toxicity (DLT) was assessed during the first 2 weeks after the 1st sonication. A subsequent expansion cohort consisted of patients treated with 9 emitters in which the primary endpoint was assessment of BBB opening on MRI using gadolinium (&amp;lt;1 hr after sonication). All patients received carboplatin either after (n=21) or before (n=12) device activation to disrupt the BBB. In addition, a sub-study was performed to investigate carboplatin concentration enhancement in the peritumoral region with sonication at time of device implantation. Results Study accrual is complete with 38 patients enrolled and 33 patients having been implanted and received at least one sonication+carboplatin. A total of 101 sonications were performed (range=1-10 sonication sessions/patient). No DLTs were observed. A total of 14 SAEs were observed including five events considered as possibly treatment related. BBB disruption was confirmed by gadolinium enhancement after sonication. In an analysis of 60 treatments in 27 patients that had all nine emitters active, 90% of activated emitters led to BBB opening in gray and/or white matter with good repeatability of BBB opening. In 3 patients who underwent intraoperative sonication and carboplatin administration, a 7.58-fold increase in brain/plasma drug levels was demonstrated. Updated and mature outcome results will be presented. Conclusion These results confirm the safety and feasibility of repeated BBB disruption using an implantable ultrasound system. LIPU substantially increases drug levels in the peritumoral brain.
P13.03.A Radiomics for the non-invasive assessment of the PDL-1 expression in patients with non-small cell lung cancer brain metastases
Authors: A Meißner, R Gutsche, N Galldiks, M Kocher, S Jünger, M Eich, L Nogova, N Schmidt, M Ruge, R Goldbrunner, M Proescholdt, S Grau, P Lohmann
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND The expression level of programmed cell death ligand 1 (PDL-1) might be an indicator for response to immunotherapy using checkpoint inhibitors in patients with non-small cell lung cancer (NSCLC). As intra-tumoral differences and discrepancies between the PDL-1 expression in the primary tumor and the brain metastases may occur, a method for a reliable non-invasive assessment of the intracranial PDL-1 expression would be of clinical value. We evaluated the potential of MRI radiomics for a non-invasive assessment of the PDL-1 expression in patients with NSCLC brain metastases. PATIENTS AND METHODS Fifty-three patients with brain metastases from NSCLC from two university brain tumor centers (group 1, 36 patients; group 2, 17 patients) underwent tumor resection with subsequent immunohistochemical assessment of the PDL-1 expression. Brain metastases were manually segmented on preoperative T1-weighted contrast-enhanced MRI. Group 1 was used for model training and validation, group 2 for model testing. After image pre-processing and radiomics feature extraction from T1-weighted contrast-enhanced MRI, a test-retest analysis was performed to identify robust features prior to feature selection. The radiomics model was trained and validated using five-fold cross validation. Finally, the best performing radiomics model was applied to the test data. Diagnostic performance was evaluated using receiver operating characteristic (ROC) analyses. RESULTS An intracranial PDL-1 expression was found by immunohistochemistry in 18 of 36 patients (50%) in group 1, and 7 of 17 patients (41%) in group 2. Univariate analysis identified tumor volume as a significant clinical feature for PDL-1 expression (area under the ROC curve (AUC), 0.77). A random forest classifier using a four-parameter radiomics signature including tumor volume yielded an AUC of 0.83 ± 0.18 in the training data (group 1). Finally, the classifier achieved an AUC of 0.84 in the external test data (group 2). CONCLUSION The developed radiomics classifiers allows a non-invasive assessment of the intracranial PD-L1 expression in patients with NSCLC brain metastases with a high diagnostic performance.
OS07.9.A Gliocova: Impact of surgeon and centre volume on 30-day mortality, readmission and risk of complication after first surgical intervention in brain tumour patients in England diagnosed between 2013-2018
Authors: R Mauricaite, M Williams
Journal: Neuro-Oncology (2022)

Abstract Background The Gliocova dataset uses linked English national cancer data on all 51,775 adult primary brain tumour patients diagnosed between 2013-2018. Here we are investigating the effect of surgeon and centre volume on post-surgical outcomes such as 30-day mortality, readmission and risk of complication. Material and Methods We selected patients from our dataset that have undergone surgical debulking or biopsy for the first time. We calculated surgeon and centre volume per 6 year period. To exclude non-tumour surgeons who might do occasional tumour cases as an emergency, we removed those that performed less than 12 operations over the 6 year period and to remove newly qualified/ near retirement surgeons we removed those that did not perform at least 1 operation within the 6 first months of 2013 and last 6 months of 2018. We developed univariate regression models to link surgeon and centre volume with 30-day mortality, readmission and risk of complication and are currently working on multivariate models including other predictors such as age, sex, Elixhauer comorbidity index, deprivation status, type of intervention (biopsy vs surgical debulking), and tumour type (i.e., Glioblastoma versus other types of brain tumours). Results We identified 29,258 patients (out of 51,775) that have undergone a surgical intervention (28,173 surgical debulking; and 1,207 biopsy). In-hospital mortality was 0.99% (N = 289), 30-day mortality was 2.3% (N = 677) and 30-day readmission was 12.7% (N = 3,725). No surgeons performed less than 1 operation during the first 6 months of 2013 or last 6 months of 2018. In univariate analyses, centre volume predicted the risk of 30-day mortality (p-value&amp;lt;0.01) and risk of complication (p-value&amp;lt;0.001), whereas surgeon volume only significantly predicted risk of complication (p-value&amp;lt;0.001). Neither surgeon volume nor centre volume were statistically significant predictors of 30-day readmission in univariate analysis. Conclusion As most surgeon and centre volume studies in brain tumour patients come from the United States, our study is one of a few in Europe to investigate this in a large adult brain tumour population. In our future work we will refine the model to account for patient factors, and assess the cost of complications and variation of these across centres, tumour types and other patient and hospital level characteristics. More information about the Gliocova project can be accessed here: https://blogs.imperial.ac.uk/gliocova/about-gliocova/. GlioCova is supported by the Imperial/NIHR BRC, and the members of the GlioCova EAG. This work uses data provided by patients and collected by the NHS as part of their care and support
P04.04.A A comprehensive genomic study of 390 H3F3A-mutant pediatric-type diffuse high-grade gliomas WHO CNS grade 4
Authors: E A Willimas, P K Brastianos, H Wakimoto, S Santagata, D P Cahill, T A Juratli
Journal: Neuro-Oncology (2022)

Abstract Background Histone gene mutant malignant gliomas - H3K27-altered diffuse midline glioma (DMG) and diffuse hemispheric glioma (DHG) H3G34-mutant - occur in all age groups and can have significant variation in clinical outcomes. Here, we report comprehensive genomic profiling from one of the largest collections of H3F3A-mutant gliomas analyzed to date, identifying subsets defined by recurrently co-mutated genes. Material and Methods We identified 390 H3F3A-mutant diffuse gliomas WHO grade 4 (201 females and 189 males) that were profiled in the comprehensive genomic profiling program at Foundation Medicine between 2013-2020. Information from pathology reports, histopathology review, and patient clinical data was assessed Results Our cohort comprised 304 (77.9%) H3K27M-mutant DMG WHO grade 4 (156 females and 148 males) and 86 H3G34-mutant DHG (45 females and 41 males) with a median age of 20 years (1- 74 years). H3K27M-mutant DMG distributed equally between pediatric and adult patients, with 52% of the patients older than 20 years, 30% older than 30 years, and 18% older than 40 years at the time of first diagnosis. Clonal FGFR1 hotspot mutations were exclusively detected in K27M-mutant DMG (n = 64/304, 21%; p=0.0001), with a significant association with a higher age at first diagnosis (median 32.5 years), and with a wide tumor distribution across the diencephalon. Additional genes which were significantly more frequently altered in K27M-mutant compared to G34-mutant diffuse gliomas included NF1 (31% vs. 8.1%; p=0.0001) and PIK3CA/PIK3R1 (27.9% vs. 15.1%; p=0.016). Conversely, targetable alterations of the cell-cycle pathway (CDK4/6 amplifications and CDKN2A/B deletions) were enriched in H3G34-mutant DHG (26%) compared to H3K27M-mutant DMG (7%). Potentially targetable PDGFR alterations were present in 32.5% of H3G34-mutant DHG and in 18% of H3K27M-mutant DMG. Conclusion These data expand our understanding of the tumor-specific molecular features of pediatric-type high-grade gliomas, identifying cohort sub-structure by recurrent co-mutations, which can inform diagnosis and clinical trial design.
P02.04.A Preoperative neutrophil, thrombocyte and monocyte to lymphocyte ratios as independent prognostic factors for patient survival in WHO 2021 glioblastoma multiforme
Authors: E Lyutfi*, G S Stoyanov*, D Dzhenkov, B D Ivanov, A Kaprelyan, P Ghenev, K Georgiev
Journal: Neuro-Oncology (2022)

Abstract Background Glioblastoma (GBM) is the most common malignant primary central nervous system (CNS) tumor. It is a fast-growing and extremely aggressive malignancy with a short postoperative survival time of little more than a year. The tumor-immune system interactions are complex and can be measured as local phenomena - e.g., tumor-infiltrating lymphocytes, or as systemic events - e.g., lymphopenia, neutropenia, etc. with cell numbers allowing for estimation of the type of immune reaction against the tumor. Material and Methods A retrospective non-clinical approach was utilized for the means of the study. Patients with a histologically and molecular verified GBM, corresponding to the guidelines of 2021 WHO CNS tumor classification, diagnosed in a three-year interval (February 2018-2021) in a single tertiary healthcare institution were included. Patients with infectious, inflammatory, autoimmune, and hematological diseases, as well as those with malignancy in another location, were excluded. Data regarding patient demographics, and preoperative peripheral blood cell counts (neutrophils, platelets, and monocytes in a ratio to lymphocytes) were compared with postoperative patient survival. Preoperative ratios were calculated as absolute values. For cutoff values we used generally accepted ones - &amp;gt;4 for neutrophil to lymphocyte (NLR), &amp;gt;200 for thrombocyte to lymphocyte (TLR), and &amp;gt;0.25 for monocyte to lymphocyte ratios (MLR). Results were statistically analyzed with MedCalc version 19.7.1 and the Kaplan-Meier method. Results A total of 22 patients fit the established criteria, with a male to female ratio of 2.14:1, mean age of 66.23 years, and mean survival of 255.72 days (8.04 months, range 24-801 days). Eight patients had an elevation of NLR and five of PLR, with no statistical correlation to survival. Six patients had an increase in MLR with a statistically significant (p=0.0044) shorter postoperative survival. Synergic increase in NLR and PLR did not show significance, while synergic increase with MLR showed no added benefit, as did comparison within MGMT promoter methylation groups. Conclusion Elevation in NLR, PLR, and MLR is a good independent prognostic marker for postoperative patient survival in histologically and mutationally verified GBM. Acknowledgments * contributed equally to the work and should be considered co-first authors.Financing: Medical University - Varna Scientific Fund, grant number 19010 and National scientific fund - young researchers (Republic of Bulgaria) grant number 2990/07.06.2021 Ethical approval: Medical University - Varna committee on scientific ethics approval protocol number 93/21.05.2020
P01.05.A Working memory performance is associated with functional connectivity between the right dlPFC and DMN in glioma patients
Authors: L Smolders, W de Baene, G Rutten, R van der Hofstad, L Florack
Journal: Neuro-Oncology (2022)

Abstract Background Patients with primary brain tumors frequently suffer from cognitive impairments in multiple domains, leading to serious consequences for socio-professional functioning and quality of life. The functional-anatomical basis of these impairments is still poorly understood. The study of correlated BOLD activity in the brain (i.e. functional connectivity) has greatly contributed to our understanding of how brain activity supports cognitive function. In particular, activity observed during the execution of specific tasks can be related to various distributed functional networks, stressing the importance of interactions between remote brain regions. Among these networks, the Default Mode Network (DMN) and the Fronto-Parietal Network (FPN) have consistently been associated with working memory performance. Recently, using task-fMRI in glioma patients, poor performance in a working memory task was associated with less deactivation of the DMN during this task and to a lack of task-evoked changes in the DMN-FPN structure. In this study, we investigated whether these effects are reflected in the resting-state (RS) functional connectivity of the same patient group, i.e. when no task was performed during fMRI. We additionally zoomed in on the part of the FPN located in the dorsolateral Prefrontal Cortex (dlPFC), since this region is believed to be mainly responsible for DMN deactivation. Material and Methods Resting-state functional MRI data were acquired pre-operatively from 45 brain tumor patients (20 low- and 25 high-grade glioma patients). Results of a pre-operative in-scanner N-back working memory fMRI task were used to assess working memory performance. Patient brains were parcellated into ROIs using both the Gordon and Yeo atlas, which have the FPN and DMN network identities readily available. The dlPFC was defined based on masks retrieved from NeuroSynth. To measure DMN-FPN functional connectivity the average Pearson correlation between the activation time series in the regions belonging to the FPN and the DMN was calculated. Functional connectivity between the DMN and the dlPFC was calculated in a similar way. Results The average correlation between the resting-state fMRI activity in the right dlPFC and in the DMN was negatively associated with working memory performance for both the Gordon atlas (p &amp;lt; 0.003) and Yeo atlas (p &amp;lt; 0.007). No association was found for the correlation between activity in the left dlPFC and the DMN, nor for the correlation between the activity in the whole FPN and the DMN. Conclusion Our findings show that working memory performance of glioma patients is related to interactions between networks that can be measured with resting-state fMRI. Furthermore, the results provide further evidence that not only specific brain regions are important for cognitive performance, but that also the interactions between large-scale networks should be considered.